The goal of the proposed research is to define brainstem neural network mechanisms that give rise to the respiratory motor patterns of airway defensive reflexes, i.e., cough and expiration reflex. Spike train analysis methods (e.g., cross-correlation, gravity) will be used to detect and evaluate functional connectivity among many simultaneously recorded neurons in cats. The plausibility of network models derived from this approach will be tested with computer simulations. Fictive cough and the expiration reflex will be evoked by mechanical stimulation of the intrathoracic trachea and larynx, respectively, in decerebrated, paralyzed, ventilated cats. Specific Aim I: Identify neurons in the nucleus tractus solitarius that relay afferent information from airway receptors eliciting cough, and define their effective connectivity with target neurons distributed in the medullary respiratory neurons, and determine their parallel and sequential responses during fictive cough. Specific Aim II: Define concurrent functional interactions among physiologically characterized medullary respiratory neurons, and determine their parallel and sequential responses during fictive cough. Specific Aim III: Identify neurons in the nucleus tractus solitarius that relay afferent information from airway receptors eliciting the expiration reflex, and define their effective connectivity with target neurons distributed in the medullary respiratory neuronal network. Specific Aim IV: Define concurrent functional interactions among physiologically characterized medullary respiratory neurons, and determine their parallel and sequential responses during fictive expiration reflex. Specific Aim V: Determine the effects of antitussive agents (codeine, dextromethorphan) on the activity of cough receptor relay neurons, medullary respiratory neurons, and their functional connectivity. Airway defensive reflexes are essential for the day-to-day survival of individuals with and without lung disease; they can also exacerbate other pathological conditions. These studies will contribute basic information that could be useful for future development of more effective therapeutic interventions for disorders involving these reflexes.